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    Association of TCF4 and CLU polymorphisms with Fuchs' endothelial dystrophy and implication of CLU and TGFBI proteins in the disease process

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    Author
    Kuot, A; Hewitt, AW; Griggs, K; Klebe, S; Mills, R; Jhanji, V; Craig, JE; Sharma, S; Burdon, KP
    Date
    2012-06-01
    Source Title
    EUROPEAN JOURNAL OF HUMAN GENETICS
    Publisher
    NATURE PUBLISHING GROUP
    University of Melbourne Author/s
    HEWITT, ALEXANDER; Jhanji, Vishal
    Affiliation
    Ophthalmology Eye And Ear Hospital
    Metadata
    Show full item record
    Document Type
    Journal Article
    Citations
    Kuot, A., Hewitt, A. W., Griggs, K., Klebe, S., Mills, R., Jhanji, V., Craig, J. E., Sharma, S. & Burdon, K. P. (2012). Association of TCF4 and CLU polymorphisms with Fuchs' endothelial dystrophy and implication of CLU and TGFBI proteins in the disease process. EUROPEAN JOURNAL OF HUMAN GENETICS, 20 (6), pp.632-638. https://doi.org/10.1038/ejhg.2011.248.
    Access Status
    Access this item via the Open Access location
    URI
    http://hdl.handle.net/11343/33010
    DOI
    10.1038/ejhg.2011.248
    Open Access at PMC
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3355250
    Description

    C1 - Journal Articles Refereed

    Abstract
    Fuchs' endothelial dystrophy (FED) is a disease affecting the corneal endothelium. Recent studies reported significant association of polymorphisms in the TCF4 (transcription factor 4) gene, and a borderline association of PTPRG (protein tyrosine phosphatase, receptor type, G) variants with late-onset FED in Caucasians from the United States. Association of TCF4 has also been reported in the Chinese population. We aimed to determine association of the reported polymorphisms in TCF4 and PTPRG, and association of polymorphisms in the candidate genes ZEB1 (zinc-finger E-box binding homoebox 1), COL8A2 (collagen, type VIII, alpha 2), TGFBI (transforming growth factor, β-induced) and CLU (clusterin) in Australian cases. We also compared the expression of TGFBI and CLU proteins between FED and normal whole corneas. In all, 30 single-nucleotide polymorphisms (SNPs) from the candidate genes were genotyped in 103 cases and 275 controls. Each SNP and haplotype was assessed for association with the disease. SNP analysis identified an association of TCF4 (rs613872 (P=5.25 × 10(-15), OR=4.05), rs9954153 (P=3.37 × 10(-7), OR=2.58), rs2286812 (P=4.23 × 10(-6), OR=2.55) and rs17595731 (P=3.57 × 10(-5), OR=3.79)), CLU (rs17466684; P=0.003, OR=1.85) and one haplotype of TGFBI SNPs (P=0.011, OR=2.29) with FED in Caucasian Australians. No evidence for genetic association of PTPRG, ZEB1 and COL8A2 was found. Immunohistochemistry showed differential expression of CLU and TGFBI proteins in FED-affected compared with normal corneas. In conclusion, variation in TCF4, CLU and TGFBI, but not PTPRG, ZEB1 and COL8A2 genes are associated with FED in Caucasian Australian cases. Differential expression of CLU and TGFBI proteins in FED-affected corneas provides novel insights into the disease mechanism.
    Keywords
    Quantitative Genetics (incl. Disease and Trait Mapping Genetics); Ophthalmology; Hearing; Vision; Speech and Their Disorders

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